(Circulation. 1999;99:942-948.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Myocardial Oxygenation During High Work States in Hearts With Postinfarction Remodeling
From the Departments of Medicine, Biochemistry, and Radiology and the Center for Magnetic Resonance Research, University of Minnesota, and the Department of Veterans Affairs Medical Center, Minneapolis, Minn.
Correspondence to Jianyi Zhang, MD, PhD, Box 508, University of Minnesota Health Science Center, 420 Delaware St SE, Minneapolis, MN 55455. E-mail zhang047{at}maroon.tc.umn.edu
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Abstract |
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Background—Postinfarction left ventricular remodeling (LVR) is associated with reductions in myocardial high-energy phosphate (HEP) levels, which are more severe in animals that develop overt congestive heart failure (CHF). During high work states, further HEP loss occurs, which suggests demand-induced ischemia. This study tested the hypothesis that inadequate myocyte oxygen availability is the basis for these HEP abnormalities.
Methods and Results—Myocardial infarction was produced by left
circumflex coronary artery ligation in swine. Studies were
performed in 20 normal animals, 14 animals with compensated LVR, and 9
animals with CHF. Phosphocreatine (PCr)/ATP was determined with
31P NMR and deoxymyoglobin (Mb-
) with 1H NMR
in myocardium remote from the infarct. Basal PCr/ATP tended
to be decreased in postinfarct hearts, and this was significant in
animals with CHF. Infusion of dobutamine (20 µg ·
kg-1 · min-1 IV) caused doubling of
the rate-pressure product in both normal and LVR hearts and
resulted in comparable significant decreases of PCr/ATP in both groups.
This decrease in PCr/ATP was not associated with detectable Mb-. In
CHF hearts, rate-pressure product increased only 40% in response
to dobutamine; this attenuated response also was not
associated with detectable Mb-.
Conclusions—Thus, the decrease of PCr/ATP during dobutamine infusion is not the result of insufficient myocardial oxygen availability. Furthermore, in CHF hearts, the low basal PCr/ATP and the attenuated response to dobutamine occurred in the absence of myocardial hypoxia, indicating that the HEP and contractile abnormalities were not the result of insufficient oxygen availability.
Key Words: myocardial infarction • phosphates • myoglobin • dobutamine • heart failure
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Introduction |
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In the failing heart, the increased systolic wall stress of the dilated left ventricle (LV) would be expected to increase energy demands, whereas oxygen delivery may be limited by an impaired coronary flow reserve. These considerations have led to the suggestion that an imbalance of the energy supply/demand relationship might contribute to impaired contractile performance in the failing heart.1 We have described a porcine model of myocardial infarction that results in LV dilation and reduced systolic performance.2 In the remodeled heart, the noninfarcted myocardium manifests high-energy phosphate (HEP) abnormalities, including decreases of creatine phosphate (PCr), ATP, the PCr/ATP ratio, and total creatine, which are most prominent in animals that develop overt congestive heart failure (CHF). Knowledge of the intracellular O2 level is necessary to understand whether oxygen limitation contributes to these HEP abnormalities in remodeled myocardium.
1H NMR spectroscopic measurements of myocardial
deoxymyoglobin (Mb-) have been used to assess mitochondrial oxygen
availability in isolated, perfused rodent hearts.3 4 We
have adapted this technique for use in canine hearts in vivo and found
no evidence of myoglobin desaturation under basal
conditions.5 However, graded coronary
stenoses caused increases of Mb- that were linearly related
to the decreases of myocardial blood flow.5 The purpose of
this study was to examine whether limited myocyte oxygen availability
contributes to the HEP changes in normal or remodeled hearts at high
work states. 31P and 1H NMR
spectroscopy were used to evaluate myocardial HEP and Mb- levels
under basal conditions, during pacing, and during
dobutamine infusion.
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Methods |
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Studies were performed in 29 swine with left circumflex coronary artery (LCx) occlusion and 20 normal animals. All experimental procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication 85-23, revised 1985).
Production of Myocardial Infarct
Young Yorkshire swine (45 days old; weight, 
10 kg) were
anesthetized with sodium pentobarbital 30 mg/kg IV, intubated,
and ventilated with a respirator. A left thoracotomy was performed, and
the proximal LCx was ligated to produce total coronary
occlusion.2 If ventricular fibrillation
occurred, electrical defibrillation was performed immediately. The
chest was then closed, and the animals were allowed to recover. Of the
29 pigs that underwent LCx ligation, 3 died before recovery from
anesthesia, 3 died during the first 2 days after surgery,
and the remaining 23 animals underwent a terminal
physiological study 6 weeks later or sooner if CHF
developed. MRI was performed 24 to 72 hours before the terminal
physiological study to characterize cardiac
performance.
Magnetic Resonance Imaging
MRI studies were performed on a Siemens Medical Vision
System operating at 1.5 T. A detailed account of the imaging and
analysis methodologies, including determination of LV chamber
volumes and ejection fractions, has been reported.2
Experimental Preparation
The swine were premedicated with ketamine HCl 20 mg/kg
IM and anesthetized with 
-chloralose 100 mg/kg followed by
20 mg · kg-1 ·
h-1 IV, intubated, and ventilated with a
respirator with supplemental oxygen. A catheter, 3.0-mm OD, was
introduced into the ascending aorta via a femoral artery. A sternotomy
was performed, and catheters were placed in the LV and the anterior
interventricular vein. A pacing electrode was sutured to
the right atrial appendage. In 5 normal pigs and 6 pigs with LCx
ligation, hydraulic occluders were placed around the left anterior
descending coronary artery (LAD). A double-tuned
(31P and 1H) 25-mm-diameter
NMR surface coil was sutured onto the LV anterior wall distant from the
infarct. The surface coil leads were connected to a balanced-tuned
circuit, and the animals were positioned in the magnet.
31P NMR Spectroscopy
Measurements were performed in a 40-cm-bore, 4.7-T magnet
interfaced with a computer console (Sisco). NMR data acquisition was
gated to the cardiac cycle.6 Radiofrequency transmission
and signal detection were performed with the surface coil. A capillary
containing 15 µL of 3 mol/L phosphonoacetic acid at the coil center
served as a reference. Chemical shifts were measured relative to PCr,
which was assigned a chemical shift of -2.55 ppm relative to 85%
phosphoric acid. Spatial localization across the LV wall was performed
with the RAPP-ISIS/FSW method.6 7 Signal origin was
restricted to a 17x17-mm column across the LV wall; within this
column, the signal was localized to 5 transmural voxels by use of the
B1 gradient.6 7
31P spectra were recorded in late
diastole with a pulse repetition time of 6 to 7 seconds.
This repetition time allowed full relaxation for ATP and inorganic
phosphate (Pi) resonances and 90% relaxation
for the PCr resonance.6 7 PCr resonance intensities were
corrected for this minor saturation. Spectra consisted of 96 scans
accumulated in a 10-minute block. Resonance intensities were integrated
by use of Sisco software. The numerical values for PCr and ATP were
expressed as ratios of PCr/ATP. Pi levels were
measured as changes from baseline values
(
Pi).
1H NMR Spectroscopy
The technique of in vivo 1H MRS detection
of Mb- has been described previously.5 Briefly, a
single-pulse collection sequence with a frequency-selective gauss
excitation pulse (1 ms) was used to excite the N- proton signal of
the proximal histidine of Mb-.8 The NMR signal was
optimized by adjusting the RF pulse power using the water signal as a
reference. A short repetition time (TR=25 ms) was used because of the
short T1 of Mb-.9 Although the short
T1 of Mb- and fast acquisition prevent gating to the
cardiac cycle, the signal loss due to motion is negligible because of
the inherently broad line width of the Mb- peak. Although the N-
proton signal is temperature-sensitive, a pilot study showed that the
chemical shift of this resonance, which appeared at 71 to 72 ppm
(relative to H2O), remained constant during
periods of coronary occlusion. Mb- data were acquired in 5
minutes (10 000 free induction decay) immediately before HEP
data acquisition.
Myocardial Blood Flow, Myocardial Oxygen Consumption, and
Lactate Measurements
Myocardial blood flow was measured with radioactive
microspheres, 15 µm in diameter, labeled with
141Ce, 51Cr,
95Nb, 85Sr, or
46Sc (NEN Corp).10 Myocardial
oxygen consumption (M
O2)
and lactate uptake were obtained by measuring oxygen and lactate
contents in aortic and anterior interventricular vein
blood. Arteriovenous oxygen and lactate differences were multiplied by
blood flow to obtain MO2
and net lactate uptake.
Tissue Preparation
At the end of the study, hearts were quickly removed, and 1
branch of the LAD was cannulated and perfused with ice-cold saline for
preparation of isolated myocytes (see below). The remainder of the
heart was fixed in 10% buffered formalin. The LV and the scar were
weighed. The region of myocardium beneath the surface coil
was sectioned into 3 transmural layers from epicardium to endocardium,
weighed, and placed into vials for counting.
Disaggregated Myocyte Measurements
To assess LV remodeling at the cellular level, myocytes from 5
hearts with left ventricular remodeling (LVR), 3 hearts
with CHF, and 7 normal hearts were isolated.11 12 The
excised specimen was perfused with calcium-free buffer gassed with 95%
O2 and 5% CO2, followed by
recirculating perfusion with 205 U/mL collagenase (type II,
Worthington Biochemical Co; 0.1% BSA, fraction V, ICN
Immuno-Biologicals) in 50 mL buffer for 20 minutes at 37°C. The
perfused tissue was gently minced with a scissors and filtered through
20-mm nylon mesh. Cells were fixed in 25%
glutaraldehyde. The yield of rod-shaped cells was 70%
to 90%.
Fifty cells (rod-shaped, with clear sarcomere striation and without membrane blebs) were used for each sample. Cell length was defined as the longest length parallel to the longitudinal axis of the cells. Cell volume was determined with a Coulter Channelyzer (model 256) connected to a Coulter Counter (model ZM). Cell cross-sectional area was calculated as cell volume divided by cell length.
Experimental Protocol
CHF was defined by the appearance of peripheral
cyanosis, ascites, and decreased activity. The remodeled group without
CHF (LVR; n=14) was studied 6 weeks after LCx ligation. Animals that
developed CHF (n=9) were studied shortly after the appearance of CHF;
earlier study was required because these animals generally died within
a few days after the appearance of CHF. Because the LVR and CHF groups
differed with respect to age and weight, each group was compared with
separate weight-matched control animals.
Aortic and LV pressures were measured with fluid-filled transducers.
Hemodynamic measurements and 31P
and 1H MRS spectra were first obtained under
basal conditions. Midway through the 20-minute data acquisition period,
a microsphere injection was performed, and blood samples were
obtained for MO2 and lactate.
The response to atrial pacing at 240 bpm was then assessed with a
physiological stimulator (model S-88, Grass
Instruments). After 10 minutes of pacing, all measurements were
repeated. Pacing was then discontinued, and the animal was allowed to
recover for 15 to 20 minutes.
The response to dobutamine 20 µg ·
kg-1 · min-1 IV
was then examined. After 10 minutes to achieve steady-state conditions,
all measurements were repeated. After completion of the above protocol,
in 5 normal pigs and 6 animals with LCx ligation, the LAD was occluded
and Mb- measurements were repeated. The hearts were then prepared
for blood flow measurements and myocyte morphological studies.
Data Analysis
Hemodynamic data were measured from the chart
recordings. Integral numerical values for PCr, ATP, and
Pi resonances were expressed as PCr/ATP and
Pi/ATP ratios. 31P NMR
spectra from the first, third, and fifth voxels were taken to
represent subepicardium, midmyocardium, and
subendocardium, respectively.
Data were compared by 1-way ANOVA with replications. A value of P<0.05 was required for significance. When a significant result was found, individual comparisons were made by the method of Scheffé. The unpaired t test was used for the comparison of data between groups. All values are expressed as mean±SEM.
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Results |
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Anatomic Data
The anatomic data are summarized in Table 1
. The ratio of LV weight to body
weight (LVW/BW) was increased 19% in LVR animals and 33% in CHF
compared with the respective controls (each P<0.05). Scar
accounted for 9% of the LV mass in the LVR group and 12% of LV mass
in the CHF group. Ratios of right ventricular weight to
body weight were increased in both experimental groups
(P<0.01).
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Arterial Substrate Levels
Arterial blood levels of glucose, lactate, and free
fatty acids were not significantly different from normal in animals
with remodeled hearts (Table 2).
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LV Volumes
LV systolic and end-diastolic volumes were
significantly increased in the remodeled groups (Table 3). Because the ejection fractions of the
2 control groups were comparable, these data were pooled. Ejection
fractions were significantly reduced in the infarcted hearts (51±3%,
41±3%, and 33±6% in the control, LVR, and CHF groups,
respectively), and the difference between LVR and CHF groups was
significant (each P<0.05, Table 3).
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Isolated Myocyte Data
In LVR hearts, mean cell length, cell volume, and cell
cross-sectional area were increased in myocytes remote from the scar
(Table 4). Myocytes from hearts with CHF
showed the greatest elongation, with no increase in cross-sectional
area.
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Hemodynamic Data
Hemodynamic variables were similar in the
normal and LVR groups, although LV end-diastolic pressure
tended to be higher in the LVR group (Table 5). Dobutamine caused
comparable increases of the rate-pressure product in the normal and
LVR groups (Table 5). CHF animals had significantly lower aortic
and LV systolic pressures and higher LV
end-diastolic pressure during the basal state (Table 5). Pacing caused a rapid increase in LV
end-diastolic pressure and a decrease of LV
systolic pressure in most of the CHF hearts, which made
complete data acquisition impossible, so that pacing data from only 2
stable preparations were obtained (data not shown). In response to
dobutamine, the CHF hearts underwent a smaller increase of
rate-pressure product than did the other groups
(P<0.05).
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Blood Flow, Lactate, and Oxygen Measurements
Myocardial blood flows were not different among the 3 groups under
basal conditions. In the normal and compensated LVR groups, blood flow
increased similarly during pacing and during dobutamine
(Table 6). The inner/outer layer blood
flow ratios (endocardial/epicardial) were not different among the
groups at baseline and remained unchanged during pacing and
dobutamine infusion. In CHF hearts, myocardial blood flow
tended to increase in response to dobutamine, but this was
not significant.
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Myocardial oxygen consumption
(MO2) was not different
between groups during basal conditions (Table 7). In the normal and LVR hearts,
MO2 increased to similar
levels in response to pacing and dobutamine. In CHF hearts,
MO2 did not increase
significantly in response to dobutamine. Lactate uptake was
similar in normal and LVR hearts under basal conditions and did not
change in response to pacing or dobutamine. Lactate
measurements obtained in 1 heart with CHF were similar to the other
groups.
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Transmural HEP and Pi Levels
Myocardial HEP and Pi data are shown in
Table 8. Baseline spectra were
characterized by high PCr and ATP levels, whereas
Pi was too low to be detected.
Dobutamine significantly increased Pi
and decreased PCr. PCr/ATP ratios in all myocardial layers were
comparable in normal and compensated LVR hearts during baseline and
paced states. In CHF hearts, basal PCr/ATP ratios were significantly
decreased. In the 2 CHF animals that completed the pacing protocol,
there were no changes in PCr/ATP ratio during pacing (data not shown).
In normal and LVR hearts, dobutamine caused significant
decrease of PCr in the epicardial and midmyocardial layers, but not in
endocardium (Table 8). In CHF hearts, PCr did not change
significantly from the already reduced baseline levels during
dobutamine, and Pi also did not
change.
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Myoglobin Saturation
The Figure shows typical
1H MRS spectra from normal, LVR, and CHF hearts.
No Mb- resonance was detected in any heart of any group under basal
conditions (panel A) or during pacing (data not shown) or
dobutamine infusion (panel B). During coronary
artery occlusion (panel C), done as a positive control to verify that
Mb- could be detected, a Mb- resonance appeared at 71 ppm upfield
of the water resonance with a high signal-to-noise ratio.
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Discussion |
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The main findings of this study can be summarized as follows. The decrease of PCr/ATP in normal and LVR hearts during dobutamine infusion was not associated with detectable myoglobin desaturation. Furthermore, the abnormally decreased PCr/ATP during basal conditions in CHF hearts was not associated with myoglobin desaturation. The data thus indicate that oxygen limitation is not the basis for the HEP abnormalities present under basal conditions in the CHF group and cannot account for the HEP changes during dobutamine stimulation in the normal and LVR groups. Taken together, the findings do not support the hypothesis that limited myocyte oxygen availability is the basis for the bioenergetic or contractile abnormalities in remodeled myocardium.
Anatomic Characteristics of the Model
Isolated myocytes remote from the scar confirmed the presence of
cellular hypertrophy in infarcted hearts, which was most
severe in the CHF group. The increased myocyte volume resulted
primarily from a striking increase in cell length, whereas
cross-sectional area was modestly increased in LVR hearts and unchanged
in CHF hearts. The predominant increase in myocyte length with little
change in diameter is in agreement with the concept that postinfarct
remodeling results in a volume-overload-type
stimulus.13
Myocardial Blood Flow and Oxygen Consumption
Both mean myocardial blood flow and the transmural distribution of
blood flow during rapid pacing were normal in hearts with LVR. During
dobutamine infusion, blood flow increased normally in LVR
hearts. The similar oxygen consumption per gram of
myocardium in normal and LVR hearts under basal conditions
and during dobutamine in the absence of myoglobin
desaturation indicates that blood flow was not limiting in these
hearts. In animals with CHF, dobutamine caused a subnormal
increase in myocardial blood flow. Our previous demonstration of normal
coronary flow reserve in this model of CHF suggests that
failure of coronary flow to increase during
dobutamine infusion was the result of failure of myocardial
demands to increase rather than inability of coronary flow to
increase.2 This is further supported by the absence of
myoglobin desaturation in these animals.
Myocyte Oxygenation
No Mb- was detected at baseline, during pacing, or during
dobutamine in any group, although significant decreases of
PCr/ATP and increases of Pi/PCr were observed
in normal and LVR groups during dobutamine. A linear
relationship between the severity of ischemia/hypoxia
and the increase of Mb- has been observed in earlier in vitro
studies.4 5 8 Furthermore, during ischemia,
myoglobin desaturation was strongly correlated with the severity of the
blood flow reduction and occurred in concert with decreases of PCr/ATP
and increases of Pi/PCr.5 NMR
sensitivity for detecting Mb- by 1H MRS and
PCr by 31P MRS is comparable.9 Also,
Mb- NMR visibility in muscle is near 100%.8 9 14 15
These considerations suggest that an Mb- resonance should be
detectable when myoglobin desaturation exceeds 10%. The
P50 for myoglobin O2
saturation at physiological temperatures is 2.5 to
5 mm Hg.3 4 16 17 If we assume that 10%
desaturation went undetected and the P50 for
myoglobin is 2.5 mm Hg, our findings indicate that the
intracellular PO2 would not have
fallen below 22 mm Hg during any intervention. Because the
Km value for O2 with
respect to cytochrome oxidase is <1 mm Hg, this
PO2 level would be expected to
make mitochondrial oxygen availability
nonlimiting.18
Although Mb- was not detected during dobutamine
infusion, it is possible that an initial period of myoglobin
desaturation at the onset of increased work could have been missed. To
achieve adequate sensitivity for detection of Mb- required summing
of 1H NMR spectra over a period of 5 minutes.
Furthermore, measurements were not obtained until steady-state
hemodynamic conditions had been achieved. If oxygen
limitation occurred at the onset of dobutamine infusion,
this might have triggered a feedback loop that would adjust contractile
activity and metabolic demands downward to match oxygen
availability. Such feedback control of HEP has been demonstrated during
acute reductions in coronary perfusion, in which the initial
loss of PCr recovers to near normal levels despite continuing
hypoperfusion.19 20 At the present time,
1H NMR technology for in vivo detection of Mb-
does not allow sufficient temporal resolution to examine the initial
time course of the response to dobutamine.
Basal-State HEP Levels
Basal PCr/ATP ratios tended to be lower than control in the LVR
group and were substantially reduced in CHF hearts.2 21
Myocardial PCr levels are related to cytosolic [ADP] levels, because
creatine kinase is a near-equilibrium enzyme and the concentrations of
the other substrates generally exceed their respective
Km values.22 Hence, the
decreased PCr/ATP in the CHF hearts probably resulted from elevated ADP
levels. However, the hypothesis that the reduction in PCr/ATP ratio
resulted from elevation of ADP secondary to a mismatch between oxygen
supply and demand is not supported by the current data. The mechanism
of this abnormality remains to be determined.
HEP Responses to Increased Work States
The increase of myocardial work during dobutamine
infusion in normal and LVR hearts resulted in significant increases of
blood flow and MO2, with no
detectable myoglobin desaturation. Thus, the decreased PCr/ATP ratios
during dobutamine infusion probably reflect a change in the
kinetics of oxidative phosphorylation or intermediary
metabolic steps rather than a myocyte
oxygenation–related limitation of ATP synthetic
capacity.23 In normal pigs, Massie et al24
reported that PCr/ATP ratios were decreased at moderately high work
states in association with a decreased endocardial-to-epicardial blood
flow ratio and lactate release. They suggested that these changes
reflected demand ischemia,24 but the present
data demonstrate that HEP changes can occur during moderately high work
states in well-oxygenated myocardium. The
reduced response to dobutamine in the CHF group may be
related to ß-adrenergic receptor downregulation25 or to
a primary decrease in myocyte contractile performance, as in
pacing-induced heart failure.26 Nevertheless, the response
of the CHF hearts to dobutamine, although reduced, was not
associated with myoglobin desaturation or changes in the already low
PCr/ATP ratios. Similarly, Schaefer et al27 observed that
dobutamine caused no change in phosphorus metabolites in
patients with dilated cardiomyopathy. The lack of
reduction of the PCr/ATP ratio or myoglobin desaturation during
dobutamine supports the view that the ability to utilize
ATP, rather than the ability to produce ATP, limited function in the
CHF group during dobutamine stimulation.
Conclusions
The decreases of PCr/ATP that occur during dobutamine
stimulation in normal and LVR hearts are not caused by insufficient
myocyte oxygen availability. In hearts with CHF, the decreased basal
PCr/ATP ratios and the reduced response to dobutamine also
were not associated with myocyte deoxygenation,
indicating that decreased oxygen availability did not constrain
function or cause the observed HEP abnormalities.
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Acknowledgments |
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This work was supported by US Public Health Service grants HL-21872, HL-33600, HL-50470, and HL-57994 and a Grant-in-Aid from the American Heart Association. Dr Zhang is the recipient of an Established Investigator Award from the American Heart Association.
Received June 5, 1998; revision received September 18, 1998; accepted September 25, 1998.
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